Process for the production of aminoazobicycloalkanes from oximes

ABSTRACT

A process for preparing a compound of formula (I), wherein n is 2 or 3; which process comprises reducing a compound of formula (II), wherein R 1  is hydrogen or C 1-4  alkyl and n is 2 or 3; by catalytic hydrogenation in the presence of a rhodium catalyst. ##STR1##

This application is the national phase of PCT/EP95/02824, filed Jul. 18,1995, issued as WO96/03401 on Feb. 8, 1996.

The present invention relates to a new process for preparing keyintermediates to pharmaceutically active compounds.

U.S. Pat. No. 4,886,808 and EP-A-247266 (Beecham Group plc) describecertain compounds which are granatane and tropane derivatives having5-HT₃ receptor antagonist activity which are described as possessing anumber of potential therapeutic utilities, including inter alia thetreatment of cytotoxic agent induced emesis. Example 6 of U.S. Pat. No.4,886,808 describes the preparation of granisetron, which is a granatanederivative and Example 5 of EP-A-247266 describes the preparation of BRL46470A, which is a tropane derivative.

GB 2125398 (Sandoz Limited) describes the preparation of granatyl aminesfrom the corresponding oxime using alane. The use of alane on a largeindustrial scale is disadvantageous, because it is usually generated bythe addition of concentrated sulphuric acid to lithium aluminiumhydride, and is a potentially hazardous reducing agent, requiringspecial precautionary measures.

The method described in EP-A-247266 for preparing the tropane side chainintermediate results in the formation of a considerable amount of theunwanted exo product. A new process has been devised which is convenientto use on an industrial scale, has a rapid reaction rate and results ina high ratio of desired endo product.

Accordingly, the present invention provides a process for preparing acompound of formula (I): ##STR2## wherein

n is 2 or 3;

which process comprises reducing a compound of formula (II): ##STR3##wherein R¹ is hydrogen or C₁₋₄ alkyl and n is 2 or 3; by catalytichydrogenation in the presence of a rhodium catalyst.

Examples of R¹ when C₁₋₄ alkyl include methyl, ethyl, propyl and butyl,in all possible isomers. Preferably R¹ is hydrogen or methyl.

Preferably n is 2.

The catalytic hydrogenation is normally carried out in an organicsolvent such as dry methanol, industrial methylated spirits, ethanol andisopropanol or an aqueous/organic solvent mixture such as in aqueousmethanol, industrial methylated spirits, ethanol and isopropanol atelevated temperature such as 25° to 70° C. preferably about 50° C. andat elevated pressure such as 20 to 200 psi (137.9 to 1379 kPa),preferably at 25 to 50 psi (172.4 to 344.8 kPa). The rhodium catalyst isusually used on a conventional support medium such as carbon.

The percentage of rhodium to carbon is usually I to 10% by weight,preferably around 5%. The catalyst is usually used in a proportion of 1to 20% by weight of the starting material, preferably at about 10%.

The reaction is optionally carried out in the presence of ammonia whichmay be added as an aqueous solution or as dry ammonia gas. The additionof ammonia gives a faster, cleaner reaction and reduces the formation ofside products. Ammonia is usually added at a molar ratio of 2:1 to 15:1to the starting material, preferably at a molar ratio of about 9:1.

Compounds of formula (II) are prepared according to conventionalprocedures, such as those described in Descriptions 1, 2 and 3.

The following Examples illustrate the present invention.

Description 1 Preparation of O-methyl-8-methyl-8-azabicyclo3.2.1!octan-3-one oxime ##STR4##

A mixture of 8-methyl-8-azabicyclo 3.2.1!octan-3-one (tropinone) (98.7g, 0.71 mole), O-methylhydroxylamine hydrochloride (71.0 g, 0.85 mole)and water (215 ml) was stirred at ambient temperature for 0.5 h. Theclear solution was basified to pH 12 with 40% aqueous NaOH and extractedwith toluene (3×400 ml). The combined organic phase was dried (K₂ CO₃),filtered and the solvent removed in vacuo. The residue was purified byfractional distillation under reduced pressure to afford the titlecompound as a colourless oil, 111.1 g (93%).

¹ H NMR (CDCl₃, JEOL 270 MHz): δ1.50 (m,2H), δ2.05 (m,4H), δ2.37 (s,3H),δ2.55 δ(m,1H), δ3.27 (m, 2H) and δ3.80 (s, 3H). Mass Spec (JEOL DX 303)CI; m/z 168 (M⁺), 137, 96, 82, 42.

Description 2 Preparation of 8-methyl-8-azabicyclo 3.2.1!octan-3-oneoxime ##STR5##

A solution of 8-methyl-8-azabicyclo 3.2.1!octan-3-one (tropinone) (2.0kg) in industrial methylated spirits (IMS) (9.0 L) was treatedportion-wise with hydroxylamine hydrochloride (1.2 kg). The resultingsuspension was stirred and heated at reflux for 2 hours then allowed tocool to ambient temperature. The product. 8-methyl-8-azabicyclo3.2.1!octan-3-one oxime hydrochloride, was filtered, washed with IMS(1.0 L) and dried in air.

The hydrochloride salt obtained above was suspended in water (11.5 L)and dichloromethane (5.0 L) and treated with potassium carbonate (3.9kg). The organic layer was separated and the aqueous layer was extractedtwice with dichloromethane (3.0 L and 2.0 L). The combined organicextracts were dried with potassium carbonate, filtered through CELITEand the solvent evaporated. The residue was triturated with ethylacetate (2.0 L), filtered and dried under vacuum to give the titlecompound (1.93 kg, 87%), as a white solid

¹ H NMR (CDCl₃, JEOL 270 MH_(z)): δ11.1 (br s,1H), δ3.3 (m,2H), δ3.0 (d,1H), δ2.65 (dd, 1H), δ2.4 (s, 3H), δ2.25 (dd, 1H), δ2.15 (d, 1H), δ2.0(m, 2H), δ1.55 (m, 2H).

¹³ C NMR (CDCl₃, JEOL 67.8 MHz): δ26.1(CH₂), δ27.0 (CH₂), δ30.8 (CH₂),δ36.8 (CH₂), δ38.8 (CH₂), δ59.8 (CH), δ60.5 (CH), δ154.5 (quat), MassSpec (JEOL DX303) EI: m/z 154, (M⁺) 137, 96, 82, 42.

Description 3 Preparation of 9-methyl-9-azabicyclo 3.3.1!nonan-3-oneoxime ##STR6##

9-Methyl-9-azabicyclo 3.3.1!nonan-3-one (77 g,: Org. Synth Coll Vol. 4,816) was added to a suspension of hydroxylamine hydrochloride (41.7 g)in ethanol (350 mls). The mixture was heated at reflux for 2 hours, thenallowed to cool to ambient temperature. The product solid was filtered,washed with ethanol (50 ml) then diethylether (200 ml) and dried in air.

The hydrochloride salt obtained above was suspended in water (390 ml anddichloromethane (110 ml) and treated with potassium carbonate (49.1 g).The organic layer was separated and the aqueous phase was extractedtwice with dichloromethane (2×110 ml).

The combined organic extracts were dried with potassium carbonate whilststirring with activated charcoal.

The mixture was filtered through CELITE and the solvent removed byevaporation under reduced pressure to give the crude free base (weightyield=34.3 g).

The crude free base was recrystallised from hot ethyl acetate (144 ml)to give the title compound as a pale yellow solid (26 g, 31%).

¹ H NMR (CDCl₃, JEOL 270 MHz): δ9.62 (br s,1H), δ3.1 (m,2H), δ3.0(s,1H), δ2.75 (dd,1H), δ2.55 (s,3H), δ2.4 (dd,1H), δ2.23 (d, 1H), δ1.95(m,2H), δ1.75 (m,1H) δ1.5 (m,3H).

EXAMPLE 1 Preparation of endo-3-amino-8-methyl-8-azabicyclo 3.2.1!octane##STR7##

A solution of O-methyl-8-methyl-8-azabicyclo 3.2.1!octan-3-one oxime(500g; 3 moles) in methanol (3.2 L) and 0.88 ammonia (1.8 L. 9. equivs) washydrogenated over 5% rhodium on carbon paste (50 g dry wt.) at 35-50 psi(241.3-344.8 kPa) and 50° C. for 16 hours. After cooling and purgingwith nitrogen, the catalyst was filtered off and washed with freshmethanol (2×500 ml). The solvent was distilled out and the residuediluted with isopropanol (1.5 L). The solvent was again distilled out toleave the title compound as an oil which was distilled (bp 86°/7 mm) togive the purified title compound as a colourless solid (344 g, 82%).

¹ H NMR (CDCl₃, JEOL 270 MHz): δ3.2 (t,1H), δ3.1 (m,2H), δ2.25 (s,3H),δ2.1 (m,2H), δ2.0 (m,4H) δ1.45 (dd,2H).

¹³ C NMR (CDCl₃ ; JEOL 67.8 MHz): δ26.2 (CH₂); δ39.4 (CH₂); δ40.4 (CH orCH₃); δ42.7 (CH or CH₃); δ60.3 (CH or CH₃) Mass Spec. (JEOL DX303) El:m/z 140 (M⁺), 124, 96, 83.

EXAMPLE 2 Preparation of endo-3-amino-8-methyl-8-azabicyclo 3.2.1!octane##STR8##

A solution of 8-methyl-8-azabicyclo 3.2.1!octan-3-one oxime (1500 g; 9.7moles) in methanol (8.2 L) and 0.88 ammonia (5.4 L 9. equivs) washydrogenated over 5% rhodium on carbon paste (50 g dry wt.) at 29-44 psi(199.8-303.4 kPa) and 50° for 17 hours. After cooling and purging withnitrogen, the catalyst was filtered off and washed with fresh methanol(2×1.5 L). The solvent was distilled out and the residue diluted withisopropanol (4 L). The solvent was again distilled out to leave thetitle compound as an oil which was distilled (bp 68°-70°/5 mm) to givethe purified title compound as a colourless solid (1.23 Kg, 90%).

¹ H NMR (CDCl₃, JEOL 270 MHz): δ3.2 (t,1H), δ3.1 (m,2H), δ2.25 (s,3H),δ2.1 (m,2H), δ2.0 (m,4H) δ1.45 (dd,2H).

¹³ C NMR (CDCl₃ ; JEOL 67.8 MHz): δ26.2 (CH₂); δ39.4 (CH₂); δ40.4(CH/CH₃); δ42.7 (CH/CH₃); δ60.3 (CH/CH₃) Mass Spec. (JEOL DX303) El; m/z140 (M⁺), 124, 96, 83.

EXAMPLE 3 Preparation of endo-3-amino-9-methyl-9-azabicyclo 3.3.1!nonane##STR9##

A solution of 9-methyl-9-azabicyclo 3.3.1!nonan-3-one oxime (10 g, 0.06moles) in methanol (70 ml) and 0.88 ammonia; (36 ml; 10.0 equivs) washydrogenated at 50° C. and 50 psi (344.8 kPa)/H₂ for 16 hrs using 5%Rhodium on carbon paste (1 g dry weight). The reaction mixture wascooled to room temperature and filtered to remove catalyst. The catalystbed was washed with methanol and the methanolic solution was thenevaporated under reduced pressure to give the title compound as an oil(8.6 g, 93% weight recovery) which solidified to a waxy solid onstanding (8.6 g, 93%).

G.C./Mass Spec. (JEOL DX303) EI: M/z 154 (M⁺)

I claim:
 1. A process for preparing a compound of formula (I): ##STR10## wherein n is 2 or 3;which process comprises reducing a compound of formula (II): ##STR11## wherein R¹ is hydrogen or C₁₋₄ alkyl and n is 2 or 3; by catalytic hydrogenation in the presence of a rhodium catalyst, provided that the yield of the undo isomer is about 82% or greater.
 2. A process according to claim 1 wherein n is
 3. 3. A process according to claim 1 wherein n is
 2. 4. A process according to claim 1 wherein R¹ is hydrogen or methyl.
 5. A process according to claim 1 wherein the catalytic hydrogenation is carried out at elevated temperature 25° to 70° C. and at elevated pressure 20 to 200 psi (137.9 to 1379 kPa).
 6. A process according to claim 5 carried out at about 50° C. and at 25 to 50 psi (172.4 to 344.8 kPa).
 7. A process according to claim 1 wherein the rhodium catalyst is supported on carbon.
 8. A process according to claim 1 wherein the reaction is carried out in the presence of ammonia.
 9. The process of claim 1 further comprising reacting the prepared compound of formula (I) with a carboxylic acid or activated carboxylic acid to form the corresponding amide derivative.
 10. A process according to claim 9 for the preparation of granisetron where the carboxylic acid is 1-methylindazole-3-carboxylic acid or an activated carboxylic acid thereof;and optionally forming a pharmaceutically acceptable salt thereof. 